
Pyridinylmethylsulfinyl benzimidazoles and analogs which belong to a group of compounds of the formula 1 are proton pump inhibitors (PPI) that are widely used for the treatment of gastro-oesophageal reflux disease (GERD) and other acid associated diseases. The first proton pump inhibitor used in the clinical practice is known by its generic name omeprazole. Chemically, it is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole and was first disclosed in EP 0005129. The other structurally related proton pump inhibitors are rabeprazole or pariprazole, pantoprazole, lansoprazole, leminoprazole, and tenatoprazole. Pyridinylmethyl-sulfinyl benzimidazoles and analogs belong to a group of chiral sulfoxides. The stereochemical structure of these compounds affects their physicochemical properties. Thus, the S-enantiomer of omeprazole commonly referred as esomeprazole (1a) is said to have improved pharmacokinetical properties which give an improved therapeutic profile such a lower degree of inter-individual variation (WO 94/27988). Esomeprazole magnesium, the generic name for magnesium bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole), is a well-known gastric proton-pump inhibitor and has been commercially available from AstraZeneca under the brand name NEXIUM™ since 2001.
Due to advantageous physiochemical properties of certain enantiomerically pure compounds there is a great need for simple and industrially applicable processes for their preparation. Enantiomerically pure compounds can be obtained either by resolution techniques or asymmetric synthesis. There are processes for resolution of different substituted 2-(2-pyridinylmethylsulphinyl)-1H-benzimidazoles disclosed in the prior art, described in DE 4035455 and WO 94/27988. The disclosed processes involve synthetic steps wherein a diastereomeric mixture is synthesized from the racemate of the corresponding substituted 2-(2-pyridinylm ethylsulphinyl)-1H-benzimidazoles. The following separation of the diastereomers involves complicated separation steps and a large amount of waste is generated.
One of the most efficient methods for enantioselective sulfoxidation is modified Sharpless procedure, developed by Kagan (Pitchen, P.; Deshmukh, M.; Dunach, E.; Kagan, H. B. J. Am. Chem. Soc. 1984, 106, 8188). The Kagan protocol is applied for the preparation of enantiomerically enriched pyridinylmethylsulfinyl benzimidazoles, especially esomeprazole, disclosed in the patent WO 96/02535. The oxidation of sulfides is carried out in an organic solvent with an oxidizing agent—a hydroperoxide derivative, preferably cumene hydroperoxide, in the presence of a titanium-diethyl tartrate catalyst and optionally in the presence of a base. The amount of catalyst is near equimolar and the method does not work well with convenient hydrogen peroxide. The patent application US 2003/0171591 describes an improved said process. Another similar method (WO 2004/052882) describes an asymmetric sulfoxidation using chiral zirconium or hafnium complex with tartaric acid esters or amides as catalysts.
The patent application WO 03/089408 discloses an asymmetric oxidation using a catalyst comprising of titanium or vanadium complexed with a chiral S-(+)- or R-(−)-methyl mandelate ligand. The general reaction conditions are similar as in the patent WO 96/02535; oxidation is performed preferably with cumene hydroperoxide in an organic solvent and in the presence of a base. Again, main deficiencies are not solved.
The patent application WO 2004/087702 describes a process for the enantioselective preparation of sulfoxides (from pyridinylmethylsulfinyl benzimidazoles or pyridinylmethylsulfinyl imidazopyridyles) using an oxidizing agent (usually aqueous H2O2 or H2O2.urea complex) in the presence of a tungsten or vanadium based catalysts with a chiral amino alcohols. The method is efficient for preparation of enantiomers of tenatoprazole while it is surprisingly less suitable for preparation of esomeprazole.
Further methods to obtain enantiopure pyridinylmethylsulfinyl benzimidazoles, especially esomeprazole, via enantioselective oxidation are described in:
IN 2003MU00503 (Abstract) indicating use of catalyst comprising Ti or V complexed with monodentate ligand;
WO 2008018091 using catalyst comprising chiral Ti isopropoxide and tartrate complex;
CN 1810803 A (Abstract) indicating use of catalyst comprising Ti alkoxide and chiral bidentate ethylene glycol complex;
WO 2007088559 using catalyst comprising V alkoxide and chiral ligand;
CN 101012141 A (Abstract) indicating use of catalyst comprising Ti or Zr alkoxide and chiral β-amino acids; and
CN 1995037 A (Abstract) indicating use of catalyst comprising tartrate and V alkoxide.
A chiral catalyst for the asymmetric oxidation comprising Schiff base ligands known as salen ligands (general formula 2) was first disclosed in the patent application WO 91/14694 by E.N. Jacobsen and coworkers and published in Journal of Organic Chemistry 1991, 56, 2296.
Jacobsen-type catalysts based on mangan-salen complexes (see general formula 2) are now routinely used in asymmetric epoxidations. However, their use in enantioselective oxidation of sulfides to sulphoxides is less explored. First disclosure of asymmetric oxidation of prochiral sulfides was published in patent application WO 93/03838, Tetrahedron Letters 1992, 33, 7111, and Chem. Lett. 1995, 335. First practical application of the said method is the preparation of armodafinil (Tetrahedron: Asymmetry 2007, 18, 2959). All published methods are focused on aryl methyl sulfides. None of the methods describes an oxidation of prochiral sulfides in which substituted aromatic or heteroaromatic rings are placed on both sides of sulphur atom as it is in the molecular structure of various proton pump inhibitors.

Another sulfoxidation of aryl methyl sulfides using vanadium-salan complexes of the formula 3 is also known (Journal of Organic Chemistry 2004, 69, 8500). However, synthesis of manganese complexes of salan ligands and their use in asymmetric oxidation is unknown.

There is still a need for an efficient method of preparation of proton pump inhibitors.